The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel

Abstract

The region consisting of the first and second variable regions (V1V2) of gp120 plays vital roles in the functioning of the HIV-1 envelope (Env). V1V2, which harbors multiple glycans and is highly sequence diverse, is located at the Env apex and stabilizes the trimeric gp120 spike on the virion surface. It shields V3 and the coreceptor binding sites in the prefusion state and exposes them upon CD4 binding. Data from the RV144 human HIV-1 vaccine trial suggested that antibody responses targeting the V1V2 region inversely correlated with the risk of infection; thus, understanding the antigenic structure of V1V2 can contribute to vaccine design. We have determined a crystal structure of a V1V2 scaffold molecule (V1V2 ZM109 -1FD6) in complex with 830A, a human monoclonal antibody that recognizes a V1V2 epitope overlapping the integrin-binding motif in V2. The structure revealed that V1V2 assumes a five-stranded beta barrel structure with the region of the integrin-binding site (amino acids [aa] 179 to 181) included in a "kink" followed by an extra beta strand. The complete barrel structure naturally presents the glycans on its outer surface and packs into its core conserved hydrophobic residues, including the Ile at position 181 which was highly correlated with vaccine efficacy in RV144. IMPORTANCEData from the RV144 phase III clinical trial suggested that the presence of antibodies to the first and second variable regions (V1V2) of gp120 was associated with the modest protection afforded by the vaccine. V1V2 is a highly variable and immunogenic region of HIV-1 surface glycoprotein gp120, and structural information about this region and its antigenic landscape will be crucial in the design of an effective HIV-1 vaccine. We have determined a crystal structure of V1V2 in complex with human MAb 830A and have shown that MAb 830A recognizes a region overlapping the ␣4␤7 integrin-binding site. We also showed that V1V2 forms a 5-stranded beta barrel, an elegant structure allowing sequence variations in the strand-connecting loops while preserving a conserved core. The HIV-1 envelope (Env) glycoprotein complex, consisting of glycoproteins gp120 and gp41, mediates the virus entry into the host cell. This heterotrimer is the major target for neutralizing antibodies (Abs) induced in HIV-1-infected patients and for HIV/ AIDS vaccine development (1). Glycoprotein gp120 has five variable and five conserved regions (2); the region consisting of the first and second variable regions (V1V2) is the most diverse in both sequence and length. V1V2, including residues 126 to 196 in the HXB2 numbering scheme (3), usually has two nested disulfide bonds; the V1 disulfide bond (between cysteine residues 131 and 157) is located within the V2 disulfide bond (between residues 126 and 196) (4). The average length of V1V2 is about 80 amino acids (aa), with a possibility of large length variations mostly derived from two regions, one in the middle of V1 and the other near the C-terminal end of V2. Recent data have shown that V1V2 is locate...

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

“…These conserved gp120 elements are not formed/exposed in the unliganded state of Env but become so after binding to CD4 or the CD4-mimetic compounds (70, 73-76, 86, 89, 95). Our results with the 830A monoclonal antibody from HIV-1-infected humans (107,108) and the 902090 monoclonal antibody from an immunized monkey also suggest that some V2 epitopes on gp120 become readily available for antibody binding after Env exposure to BNM-III-170 binding. The V2i antibody 830A recognizes a discontinuous epitope on the surface of a ␤-barrel composed of V2 strands (108).…”

“…Our results with the 830A monoclonal antibody from HIV-1-infected humans (107,108) and the 902090 monoclonal antibody from an immunized monkey also suggest that some V2 epitopes on gp120 become readily available for antibody binding after Env exposure to BNM-III-170 binding. The V2i antibody 830A recognizes a discontinuous epitope on the surface of a ␤-barrel composed of V2 strands (108). The C strand (residues 171 to 177) of this V2 ␤-barrel is recognized by the 902090 antibody.…”

“…Two human monoclonal antibodies (CH22 and CH23) directed against the gp120 V3 region were derived from subjects in the RV135 clinical HIV-1 vaccine trial (106). The 830A antibody, derived from an HIV-1-infected individual, recognizes a discontinuous epitope comprising residues from the gp120 V2 region (107,108). None of the monoclonal antibodies neutralized untreated HIV-1 JR-FL (Table 4).…”

Rationally Designed Immunogens Targeting HIV-1 gp120 V1V2 Induce Distinct Conformation-Specific Antibody Responses in Rabbits

“…Glycoprotein gp120 has been conventionally divided into five variable and five conserved regions (3), and the region of the first and second variable loops (V1V2) is the most diverse region of Env in both sequence and length (4). However, recent data have shown that V1V2 can form, in the structurally constrained scaffolded V1V2 or the stabilized BG505 SOSIP.664 trimer, a unique five-stranded ␤-barrel structure with strands A, B, C, C=, and D (5,6). In the trimer context, the V1V2 domain is located at the apex of the Env trimer, and the three V1V2 regions in the trimer join together at the center to form a top layer of the Env complex (5,(7)(8)(9).…”

“…V1V2 also harbors a putative integrin-binding site that may also mediate Env binding to host cells (12)(13)(14). One such site, the tripeptide LD(I/V) motif at amino acid positions 179 to 181 (HxB2 numbering) (15), is located at the beginning of the C= strand in the ␤-barrel (6).…”